{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T04:54:41Z","timestamp":1791608081914,"version":"4.3.4"},"reference-count":102,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T00:00:00Z","timestamp":1770940800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001407","name":"Department of Biotechnology (DBT), Government of India, New Delhi","doi-asserted-by":"publisher","award":["BT\/PR45527\/MED\/122\/322\/2022"],"award-info":[{"award-number":["BT\/PR45527\/MED\/122\/322\/2022"]}],"id":[{"id":"10.13039\/501100001407","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Parkinson\u2019s Disease & Movement Disorder Research Fund (PDMDRF), NIMHANS"},{"name":"CSIR Ph.D. fellowship"},{"name":"UGC NET-JRF Ph.D. fellowship"},{"name":"YSS\u2013ICMR-DHR"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Mutations in leucine-rich repeat kinase 2 (LRRK2) are among the most common genetic causes of Parkinson\u2019s disease (PD), yet substantial heterogeneity exists among pathogenic variants. How mutations in distinct functional domains of LRRK2 differentially perturb cellular homeostasis remains incompletely understood. Here, we compared two pathogenic LRRK2 mutations\u2014G2019S in the kinase domain and I1371V in the GTPase domain\u2014across multiple cellular models, including SH-SY5Y and U87 cells, and healthy human iPSC-derived floor plate cells. We demonstrate that the I1371V mutation induces markedly more severe cellular dysfunction than G2019S. I1371V-expressing cells exhibited elevated LRRK2 autophosphorylation at S1292 and robust hyperphosphorylation of Rab8A and Rab10, indicating enhanced downstream signaling. These alterations impaired sterol trafficking, leading to selective depletion of membrane cholesterol without changes in total cellular cholesterol. Consequently, I1371V cells displayed increased membrane fluidity, disrupted microdomain organization, altered membrane topology, reduced caveolin-1 expression, and impaired dopamine transporter surface expression and dopamine uptake. Lipidomic profiling further revealed a broad disruption of lipid homeostasis, including reductions in cholesteryl esters, sterols, sphingolipids, and glycerophospholipids, whereas G2019S cells showed comparatively modest changes. Pharmacological intervention revealed mutation-specific responses, with the non-selective LRRK2 modulator GW5074 outperforming the kinase-selective inhibitor MLi-2 in restoring Rab8A phosphorylation, membrane integrity, and dopaminergic function. Collectively, these findings identify membrane lipid dysregulation as a central cell biological mechanism in LRRK2-associated PD and underscore the importance of variant-specific therapeutic strategies.<\/jats:p>","DOI":"10.3390\/cells15040342","type":"journal-article","created":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T16:09:32Z","timestamp":1770998972000},"page":"342","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Membrane Dysfunction as a Central Mechanism in LRRK2-Associated Parkinson\u2019s Disease: Comparative Analysis of G2019S and I1371V Variants"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-7867-7554","authenticated-orcid":false,"given":"Khushboo","family":"Singh","sequence":"first","affiliation":[{"name":"Department of Biophysics, National Institute of Mental Health and Neurosciences, Institute of National Importance, Bengaluru 560029, Karnataka, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roon","family":"Banerjee","sequence":"additional","affiliation":[{"name":"Department of Biophysics, National Institute of Mental Health and Neurosciences, Institute of National Importance, Bengaluru 560029, Karnataka, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandrakanta","family":"Potdar","sequence":"additional","affiliation":[{"name":"Department of Biophysics, National Institute of Mental Health and Neurosciences, Institute of National Importance, Bengaluru 560029, Karnataka, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anisha","family":"Shaw","sequence":"additional","affiliation":[{"name":"Department of Biophysics, National Institute of Mental Health and Neurosciences, Institute of National Importance, Bengaluru 560029, Karnataka, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rakshith","family":"Rakshith","sequence":"additional","affiliation":[{"name":"Department of Biophysics, National Institute of Mental Health and Neurosciences, Institute of National Importance, Bengaluru 560029, Karnataka, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7933-8826","authenticated-orcid":false,"given":"Nitish","family":"Kamble","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Institute of Mental Health and Neurosciences, Institute of National Importance, Bengaluru 560029, Karnataka, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3634-2219","authenticated-orcid":false,"given":"Vikram","family":"Holla","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Institute of Mental Health and Neurosciences, Institute of National Importance, Bengaluru 560029, Karnataka, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8016-9089","authenticated-orcid":false,"given":"Ravi","family":"Yadav","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Institute of Mental Health and Neurosciences, Institute of National Importance, Bengaluru 560029, Karnataka, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pramod Kumar","family":"Pal","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Institute of Mental Health and Neurosciences, Institute of National Importance, Bengaluru 560029, Karnataka, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8864-473X","authenticated-orcid":false,"given":"Indrani","family":"Datta","sequence":"additional","affiliation":[{"name":"Department of Biophysics, National Institute of Mental Health and Neurosciences, Institute of National Importance, Bengaluru 560029, Karnataka, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1212\/01.WNL.0000167552.79769.b3","article-title":"LRRK2 gene in Parkinson disease: Mutation analysis and case-control association study","volume":"65","author":"Lang","year":"2005","journal-title":"Neurology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1857","DOI":"10.1002\/mds.27527","article-title":"Genotype-phenotype relations for the Parkinson\u2019s disease genes SNCA, LRRK2, VPS35: MDSGene systematic review","volume":"33","author":"Trinh","year":"2018","journal-title":"Mov. 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